Pavlovian fear conditioning has proved to be a useful model for the study of the cellular mechanisms of fear learning and memory. Considerable progress has been made in understanding the neural mechanisms that support this form of learning, but very little is known about how fear memories persist in the face of protein turnover. The amygdala is thought to be critical to the acquisition and storage of fear memory, but how this occurs at the cellular level has yet to have been fully answered. Recent studies suggest that protein kinase M zeta (PKM6) becomes persistently active following learning and may support synaptic activity underlying the maintenance of long-term memories. The work in this proposal is designed to explore several questions about how fear memories are maintained in the amygdala. We will test if the deficits in memory following PKM6 inhibition are permanent and if amygdala-dependent fear memories rely on PKM6 activity regardless of the age of the memory. We will also test the hypothesis that the maintenance of fear memory in the amygdala is supported by the trafficking of GluR2 containing 1-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors, which is thought to be controlled by PKM6. Finally, we will use lentiviral vectors to determine if neurons that are involved in the initial acquisition of fear memory are the same cells that use PKM6 to maintain the memory. The long-term goal of the work in this proposal is to reach a better understanding of the fundamental issue of how memories are stored in the brain. The work in this proposal is potentially very useful in coming to a full understanding of how various organic amnesias and psychopathologies develop and persist. PUBLIC HEALTH RELEVANCE: The long-term goal of the work in this proposal is to reach a better understanding of the fundamental issue of how memories are stored in the brain. The work in this proposal is potentially very useful in coming to a full understanding of how various organic amnesias and psychopathologies develop and persist.